Distal renal tubular acidosis in mice that lack the forkhead transcription factor Foxi1
Sandra Rodrigo Blomqvist, … , Göran Bergström, Sven Enerbäck
Sandra Rodrigo Blomqvist, … , Göran Bergström, Sven Enerbäck
Published June 1, 2004
Citation Information: J Clin Invest. 2004;113(11):1560-1570. https://doi.org/10.1172/JCI20665.
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Article Nephrology

Distal renal tubular acidosis in mice that lack the forkhead transcription factor Foxi1

Abstract

While macro- and microscopic kidney development appear to proceed normally in mice that lack Foxi1, electron microscopy reveals an altered ultrastructure of cells lining the distal nephron. Northern blot analyses, cRNA in situ hybridizations, and immunohistochemistry demonstrate a complete loss of expression of several anion transporters, proton pumps, and anion exchange proteins expressed by intercalated cells of the collecting ducts, many of which have been implicated in hereditary forms of distal renal tubular acidosis (dRTA). In Foxi1-null mutants the normal epithelium with its two major cell types — principal and intercalated cells — has been replaced by a single cell type positive for both principal and intercalated cell markers. To test the functional consequences of these alterations, Foxi1–/– mice were compared with WT littermates in their response to an acidic load. This revealed an inability to acidify the urine as well as a lowered systemic buffer capacity and overt acidosis in null mutants. Thus, Foxi1–/– mice seem to develop dRTA due to altered cellular composition of the distal nephron epithelium, thereby denying this epithelium the proper gene expression pattern needed for maintaining adequate acid-base homeostasis.

Authors

Sandra Rodrigo Blomqvist, Hilmar Vidarsson, Sharyn Fitzgerald, Bengt R. Johansson, Anna Ollerstam, Russell Brown, A. Erik G. Persson, Göran Bergström, Sven Enerbäck

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Figure 4

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In confocal images of WT kidney sections, β-intercalated cells stain pos...
In confocal images of WT kidney sections, β-intercalated cells stain positive for Pds (green) and AE4 (blue) at their apical and basolateral border, respectively. Principal cells stain positive for AQP2 (orange) at their apical aspect (A). While AE4 staining is absent in Foxi1–/– kidneys (B) (lumen marked with a dashed white line), AQP2 signals are present in both WT and Foxi1–/– sections (C). AQP2 appears to stain a high fraction of epithelial cells in Foxi1–/– sections (right panel), as compared with WT (left panel) (C). ATP6B1 is absent from distal nephron epithelia in Foxi1–/– mice both in cortex (right panels) (D and E) and medulla (right panels) (F and G), as compared with WT (left panels) (D–G). Scale bars: 10 ∝m.